RESUMEN
AIMS: Insufficient erythropoietin (EPO) synthesis is a relevant cause of renal anaemia in patients with chronic kidney disease. Molidustat, a selective hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, increases endogenous EPO levels dose dependently in preclinical models. We examined the pharmacokinetics, safety, tolerability and effect on EPO levels of single oral doses of molidustat in healthy male volunteers. METHODS: This was a single-centre, randomized, single-blind, placebo-controlled, group-comparison, dose-escalation study. Molidustat was administered at doses of 5, 12.5, 25, 37.5 or 50 mg as a polyethylene glycol-based solution. RESULTS: In total, 45 volunteers received molidustat and 14 received placebo. Molidustat was absorbed rapidly, and the mean maximum plasma concentration and area under the concentration-time curve increased dose dependently. The mean terminal half-life was 4.64-10.40 h. A significant increase in endogenous EPO was observed following single oral doses of molidustat of 12.5 mg and above. Geometric mean peak EPO levels were 14.8 IU l-1 (90% confidence interval 13.0, 16.9) for volunteers who received placebo and 39.8 IU l-1 (90% confidence interval: 29.4, 53.8) for those who received molidustat 50 mg. The time course of EPO levels resembled the normal diurnal variation in EPO. Maximum EPO levels were observed approximately 12 h postdose and returned to baseline after approximately 24-48 h. All doses of molidustat were well tolerated and there were no significant changes in vital signs or laboratory safety parameters. CONCLUSIONS: Oral administration of molidustat to healthy volunteers elicited a dose-dependent increase in endogenous EPO. These results support the ongoing development of molidustat as a potential new treatment for patients with renal anaemia.
Asunto(s)
Anemia/tratamiento farmacológico , Prolina Dioxigenasas del Factor Inducible por Hipoxia/antagonistas & inhibidores , Inhibidores de Prolil-Hidroxilasa/administración & dosificación , Pirazoles/administración & dosificación , Insuficiencia Renal Crónica/complicaciones , Triazoles/administración & dosificación , Administración Oral , Adulto , Anemia/sangre , Anemia/etiología , Área Bajo la Curva , Eritropoyetina/sangre , Semivida , Voluntarios Sanos , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Masculino , Inhibidores de Prolil-Hidroxilasa/efectos adversos , Inhibidores de Prolil-Hidroxilasa/farmacocinética , Prueba de Estudio Conceptual , Pirazoles/efectos adversos , Pirazoles/farmacocinética , Insuficiencia Renal Crónica/sangre , Método Simple Ciego , Triazoles/efectos adversos , Triazoles/farmacocinética , Adulto JovenRESUMEN
BACKGROUND: Blocking the costimulatory pathway by CTLA-4 Ig, reactive with both B7-1 and B7-2 costimulatory molecules, protects the kidney during acute ischemia/reperfusion injury. This study investigated whether and how B7-1 and/or B7-2 proteins are involved in renal ischemia/reperfusion injury (IRI). METHODS: Uninephrectomized rats were submitted to warm renal ischemia (30 min) and received control monoclonal antibody (mAb; 17E3), anti-B7-1 (3H5), anti-B7-2 (24F), a combination of anti-B7-1/B7-2, or CTLA-4 Ig. Renal function, morphology, and the kinetics of inflammatory cells were studied for a ten-day period. Binding sites of the injected antibodies were detected by secondary staining with anti-mouse Ab. RESULTS: Compared with controls, acute renal failure (ARF) in the anti-B7-1 group was attenuated both functionally and morphologically. Anti-B7-1/B7-2 and CTLA-4 Ig also were protective in IRI. ARF was not altered by anti-B7-2 treatment. Two hours after reperfusion, B7-1 was expressed along the endothelial cells of the ascending vasa recta. Expression of B7-1 increased over time during the first 24 hours and decreased thereafter. Two hours after reperfusion, adherence/accumulation of T cells and monocytes/macrophages was found in the vasa recta of the ischemic kidney. Anti-B7-1-treated animals had fewer T cells and monocytes/macrophages in the vasa recta compared with controls. Leukocyte accumulation in these vessels after anti-B7-2 treatment was not different from IRI controls. CONCLUSION: These observations strongly support the key role of the B7-1 protein in the protection of renal IRI through inhibition of T cell and monocyte adherence at the level of the ascending vasa recta.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Antígeno B7-1/inmunología , Inmunoconjugados , Isquemia/fisiopatología , Monocitos/fisiología , Circulación Renal , Abatacept , Lesión Renal Aguda/patología , Lesión Renal Aguda/fisiopatología , Animales , Antígenos CD/inmunología , Antígenos de Diferenciación/farmacología , Arteriolas , Antígeno B7-1/metabolismo , Antígeno B7-2 , Antígenos CD28/metabolismo , Antígeno CTLA-4 , Adhesión Celular/efectos de los fármacos , Citometría de Flujo , Inmunohistoquímica , Isquemia/patología , Riñón/patología , Riñón/fisiopatología , Leucocitos/metabolismo , Leucocitos/patología , Masculino , Glicoproteínas de Membrana/inmunología , Necrosis , Ratas , Ratas Endogámicas Lew , Valores de Referencia , Daño por Reperfusión/patología , Daño por Reperfusión/fisiopatologíaRESUMEN
Prolactin, luteinising hormone, follicle-stimulating hormone, 17beta-oestradiol, and testosterone were measured from sera of 307 sterility patients with anovulatory cycles or amenorrhea, among them 32 women with galactorrhoea. Hyperprolactinaemia, with values being between 720 mU and 38.000 mU of prolactin/L, was recorded from 34 patients (11.1 per cent). Increased prolactin levels were recordable from 14 patients with galactorrhoea (43.8 per cent). Gonadotrophins in patients with hyperprolactinaemia were normal in 15 cases and drastically reduced in 19. Strongly reduced 17beta-oestradiol values were measured, at the same time, in eight cases. The above results were matched against literature data.
Asunto(s)
Infertilidad Femenina/diagnóstico , Prolactina/sangre , Amenorrea/diagnóstico , Anovulación/diagnóstico , Estradiol/sangre , Femenino , Hormona Folículo Estimulante/sangre , Galactorrea/complicaciones , Humanos , Infertilidad Femenina/sangre , Hormona Luteinizante/sangre , EmbarazoRESUMEN
It is reported on 155 fine needle aspiration biopsies of the thyroid gland which above all were performed in cold nodes. In 81.9% of the cases unconspicuous cell pictures or cystico-regressive changes were present. Of the 17 findings suspicuous of malignoma (11%) hitherto 2 could histologically be diagnosed as carcinomas and 3 as adenomas with considerable regressive changes. The additionally established frequency of nodular strumas and cold nodes in 547 scintigraphically examined patients had the results of 54% nodular strumas and 48.4% of cold nodes in the total material. In 90.2% the nodular strumas revealed cold nodes. The rate of malignomas of all preparations of operations of the thyroid gland was altogether at 2.9% subtracting the secondary malignant processes 2.4% were found. These findings as well as the positive data from literature give the fine needle aspiration biopsy an important role in supplementing the morphologic diagnostics and the early recognition of malignomas of the thyroid gland.